Skip to main content

Advertisement

SpringerLink
Log in

The lipoxin A4 agonist BML-111 attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats

  • Original Article
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Sepsis is a systemic inflammatory response associating severe infection leading to multi-organ failure, such as hepatic dysfunction. This study investigates the possible hepatoprotective effect of the lipoxin A4 agonist (BML-111) in cecal ligation and puncture (CLP) model in rats. Pretreatment with BML-111 (1 mg/kg, i.p., 1 h before CLP) protected against CLP-induced mortality after 24 h. BML-111 prevented marked inflammatory cells in liver tissues and decreased elevation in serum hepatic biomarkers [alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), gamma-glutamyl transferase (γ-GT)] induced by CLP. Additionally, BML-111 attenuated elevated serum level of interleukin-6 (IL-6) and downregulated hepatic IL-6 mRNA expression. Meanwhile, BML-111 further increased serum IL-10 and upregulated hepatic IL-10 mRNA expression, while it downregulated hepatic mRNA expression of nuclear factor inhibitory protein kappa-B alpha (NFκBia), toll-like receptor-4 (TLR-4), and 5-lipooxygenase (5-LOX). Moreover, BML-111 prevented NF-κB/p65 nuclear translocation and activation. In conclusion, BML-111 attenuated CLP-induced acute hepatic dysfunction through its anti-inflammatory effect by decreasing NF-κB activity, TLR-4, and 5-LOX expression with subsequent decrease in pro-inflammatory IL-6 and elevation in anti-inflammatory IL-10.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CLP:

Cecal ligation and puncture

NFκBia:

Nuclear factor inhibitory protein kappa-B alpha

References

  • Bergmeyer HU, Horder M, Rej R (1986a) International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 2. IFCC method for aspartate aminotransferase (L-aspartate: 2-oxoglutarate aminotransferase, EC 2.6.1.1). Journal of clinical chemistry and clinical biochemistry Zeitschrift fur klinische Chemie und klinische Biochemie 24:497–510

    CAS  PubMed  Google Scholar 

  • Bergmeyer HU, Horder M, Rej R (1986b) International Federation of Clinical Chemistry (IFCC) Scientific Committee, Analytical Section: approved recommendation (1985) on IFCC methods for the measurement of catalytic concentration of enzymes. Part 3. IFCC method for alanine aminotransferase (L-alanine: 2-oxoglutarate aminotransferase, EC 2.6.1.2). Journal of clinical chemistry and clinical biochemistry Zeitschrift fur klinische Chemie und klinische Biochemie 24:481–495

    CAS  PubMed  Google Scholar 

  • Brooks HF, Osabutey CK, Moss RF, Andrews PL, Davies DC (2007) Caecal ligation and puncture in the rat mimics the pathophysiological changes in human sepsis and causes multi-organ dysfunction. Metab Brain Dis 22:353–373. doi:10.1007/s11011-007-9058-1

    Article  CAS  PubMed  Google Scholar 

  • Bu Y, Yu J (2015) Rosiglitazone protects against endotoxin-induced acute liver injury in rats. Zhonghua Yi Xue Za Zhi 95:3180–3183

    CAS  PubMed  Google Scholar 

  • Chen S (2011) Natural products triggering biological targets—a review of the anti-inflammatory phytochemicals targeting the arachidonic acid pathway in allergy asthma and rheumatoid arthritis. Curr Drug Targets 12:288–301

    Article  CAS  PubMed  Google Scholar 

  • Dangi A, Huang C, Tandon A, Stolz D, Wu T, Gandhi CR (2016) Endotoxin-stimulated rat hepatic stellate cells induce autophagy in hepatocytes as a survival mechanism. J Cell Physiol 231:94–105. doi:10.1002/jcp.25055

    Article  CAS  PubMed  Google Scholar 

  • Deng Y et al (2013) Toll-like receptor 4 mediates acute lung injury induced by high mobility group box-1. PLoS One 8:e64375. doi:10.1371/journal.pone.0064375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fan L, Wang K, Shi Z, Die J, Wang C, Dang X (2011) Tetramethylpyrazine protects spinal cord and reduces inflammation in a rat model of spinal cord ischemia-reperfusion injury. J Vasc Surg 54:192–200. doi:10.1016/j.jvs.2010.12.030

    Article  PubMed  Google Scholar 

  • Ferro MM, Angelucci ME, Anselmo-Franci JA, Canteras NS, Da Cunha C (2007) Neuroprotective effect of ketamine/xylazine on two rat models of Parkinson’s disease. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas / Sociedade Brasileira de Biofisica [et al.] 40:89–96

    CAS  Google Scholar 

  • Garber CC (1981) Jendrassik–Grof analysis for total and direct bilirubin in serum with a centrifugal analyzer. Clin Chem 27:1410–1416

    CAS  PubMed  Google Scholar 

  • Gavins FN, Hughes EL, Buss NA, Holloway PM, Getting SJ, Buckingham JC (2012) Leukocyte recruitment in the brain in sepsis: involvement of the annexin 1-FPR2/ALX anti-inflammatory system. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 26:4977–4989. doi:10.1096/fj.12-205971

    Article  CAS  Google Scholar 

  • Groger M et al (2016) Monocyte-induced recovery of inflammation-associated hepatocellular dysfunction in a biochip-based human liver model. Scientific reports 6:21868. doi:10.1038/srep21868

    Article  PubMed  PubMed Central  Google Scholar 

  • Harvey SA, Dangi A, Tandon A, Gandhi CR (2013) The transcriptomic response of rat hepatic stellate cells to endotoxin: implications for hepatic inflammation and immune regulation. PLoS One 8:e82159. doi:10.1371/journal.pone.0082159

    Article  PubMed  PubMed Central  Google Scholar 

  • Kim SJ, Park JS, Lee DW, Lee SM (2016) Trichostatin A protects liver against septic injury through inhibiting toll-like receptor signaling. Biomol Ther. doi:10.4062/biomolther.2015.176

    Google Scholar 

  • Kong X, Wu SH, Zhang L, Chen XQ (2015) Roles of lipoxin A4 receptor activation and anti-interleukin-1beta antibody on the toll-like receptor 2/mycloid differentiation factor 88/nuclear factor-kappaB pathway in airway inflammation induced by ovalbumin. Mol Med Rep 12:895–904. doi:10.3892/mmr.2015.3443

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li M et al (2015) Oral administration of escin inhibits acute inflammation and reduces intestinal mucosal injury in animal models. Evidence-based complementary and alternative medicine : eCAM 2015:503617. doi:10.1155/2015/503617

    Google Scholar 

  • Liu H, Liu Z, Zhao S, Sun C, Yang M (2015) Effect of BML-111 on the intestinal mucosal barrier in sepsis and its mechanism of action. Mol Med Rep 12:3101–3106. doi:10.3892/mmr.2015.3746

    CAS  PubMed  Google Scholar 

  • Murakami T, Suzuki K, Tamura H, Nagaoka I (2011) Suppressive action of resolvin D1 on the production and release of septic mediators in D-galactosamine-sensitized endotoxin shock mice. Experimental and therapeutic medicine 2:57–61. doi:10.3892/etm.2010.170

    CAS  PubMed  Google Scholar 

  • Nullens S et al (2016) Beneficial effects of anti-interleukin-6 antibodies on impaired gastrointestinal motility, inflammation and increased colonic permeability in a murine model of sepsis are most pronounced when administered in a preventive setup. PloS One 11:e0152914. doi:10.1371/journal.pone.0152914

    Article  PubMed  PubMed Central  Google Scholar 

  • Persijn JP, van der Slik W (1976) A new method for the determination of gamma-glutamyltransferase in serum. Journal of clinical chemistry and clinical biochemistry Zeitschrift fur klinische Chemie und klinische Biochemie 14:421–427

    CAS  PubMed  Google Scholar 

  • Petronilho F et al (2012) Gastrin-releasing peptide receptor antagonism induces protection from lethal sepsis: involvement of toll-like receptor 4 signaling. Molecular medicine (Cambridge, Mass) 18:1209–1219. doi:10.2119/molmed.2012.00083

    CAS  Google Scholar 

  • Rivera CA, Gaskin L, Singer G, Houghton J, Allman M (2010) Western diet enhances hepatic inflammation in mice exposed to cecal ligation and puncture. BMC Physiol 10:20. doi:10.1186/1472-6793-10-20

    Article  PubMed  PubMed Central  Google Scholar 

  • Shafik NM, Mohamed DA, Bedder AE, El-Gendy AM (2015) Significance of tissue expression and serum levels of angiopoietin-like protein 4 in breast cancer progression: link to NF-kappaB /P65 activity and pro-inflammatory cytokines. Asian Pacific journal of cancer prevention : APJCP 16:8579–8587

    Article  PubMed  Google Scholar 

  • Sordi R, Menezes-de-Lima O Jr, Horewicz V, Scheschowitsch K, Santos LF, Assreuy J (2013) Dual role of lipoxin A4 in pneumosepsis pathogenesis. Int Immunopharmacol 17:283–292. doi:10.1016/j.intimp.2013.06.010

    Article  CAS  PubMed  Google Scholar 

  • Souza DG et al (2007) The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice. Journal of Immunology (Baltimore, Md : 1950) 179:8533–8543

    Article  CAS  Google Scholar 

  • Takahashi W et al (2013) Kinetics and protective role of autophagy in a mouse cecal ligation and puncture-induced sepsis. Critical care (London, England) 17:R160. doi:10.1186/cc12839

    Article  Google Scholar 

  • Tsai TN et al (2015) Role of exogenous Hsp72 on liver dysfunction during sepsis. Biomed Res Int 2015:508101. doi:10.1155/2015/508101

    PubMed  PubMed Central  Google Scholar 

  • Vazquez E et al (2015) Systemic changes following carrageenan-induced paw inflammation in rats. Inflammation research : official journal of the European Histamine Research Society [et al.] 64:333–342. doi:10.1007/s00011-015-0814-0

    Article  CAS  Google Scholar 

  • Walker J, Dichter E, Lacorte G, Kerner D, Spur B, Rodriguez A, Yin K (2011) Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Shock (Augusta, Ga) 36:410–416. doi:10.1097/SHK.0b013e31822798c1

    Article  CAS  Google Scholar 

  • Wang D, Yin Y, Yao Y (2015) Advances in sepsis-associated liver dysfunction. Burns & Trauma 2:97–105. doi:10.4103/2321-3868.132689

    CAS  Google Scholar 

  • Wang L, Kang F, Li J, Zhang J, Shan B (2013) Overexpression of p65 attenuates celecoxib-induced cell death in MDA-MB-231 human breast cancer cell line. Cancer Cell Int 13:14. doi:10.1186/1475-2867-13-14

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang YZ et al (2014a) BML-111, a lipoxin receptor agonist, ameliorates ‘two-hit’-induced acute pancreatitis-associated lung injury in mice by the upregulation of heme oxygenase-1. Artificial cells, nanomedicine, and biotechnology 42:110–120. doi:10.3109/21691401.2013.794355

    Article  PubMed  Google Scholar 

  • Wang YZ, Zhang YC, Cheng JS, Ni Q, Li PW, Han W, Zhang YL (2014b) Protective effects of BML-111 on cerulein-induced acute pancreatitis-associated lung injury via activation of Nrf2/ARE signaling pathway. Inflammation 37:1120–1133. doi:10.1007/s10753-014-9836-y

    Article  CAS  PubMed  Google Scholar 

  • Wu B, Walker J, Spur B, Rodriguez A, Yin K (2015a) Effects of lipoxin A4 on antimicrobial actions of neutrophils in sepsis. Prostaglandins Leukot Essent Fat Acids 94:55–64. doi:10.1016/j.plefa.2014.11.005

    Article  CAS  Google Scholar 

  • Wu KH et al (2015b) Time-series expression of toll-like receptor 4 signaling in septic mice treated with mesenchymal stem cells. Shock (Augusta, Ga). doi:10.1097/shk.00000s00000000546

    Google Scholar 

  • Yan J, Li S, Li S (2014) “The role of the liver in sepsis”. Int Rev Immunol 33:498–510. doi:10.3109/08830185.2014.889129

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Delta University for Science and Technology, Gamasa, Egypt

    Ghada S. El-Tanbouly & Hassan A. El-Kashef

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt

    Mohammed S. El-Awady, Hassan A. El-Kashef & Hatem A. Salem

  3. Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    Nermeen A. Megahed

Authors
  1. Ghada S. El-Tanbouly
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammed S. El-Awady
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nermeen A. Megahed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hassan A. El-Kashef
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hatem A. Salem
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mohammed S. El-Awady.

Ethics declarations

Ethical approval

All procedures performed were in accordance with the ethical standards of the Research Ethics Committee, Faculty of Pharmacy, Mansoura University, Egypt.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-Tanbouly, G.S., El-Awady, M.S., Megahed, N.A. et al. The lipoxin A4 agonist BML-111 attenuates acute hepatic dysfunction induced by cecal ligation and puncture in rats. Naunyn-Schmiedeberg's Arch Pharmacol 390, 361–368 (2017). https://doi.org/10.1007/s00210-016-1335-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-016-1335-2

Keywords

Search

Navigation